PROJECT SUMMARY. Effective responses in Fc-dependent, antibody-mediated anti-viral host defense require efficient and productive interactions between the cell-type specific Fc receptors of the host and anti- SARS-CoV-2 antibody. The apparent lack of effective responses in some patients represents both an opportunity and a critical challenge to delineate the mechanistic basis for such differences. Genetic inquiry can identify the contributions that the host brings to these differences. Preliminary data, presented in our parent U01, indicate that nearly one-third of persons have structural variants (SV) in the classical Fc locus in addition to the prevalent single nucleotide polymorphisms affecting affinity of ligand binding, receptor mobility in the plane of the cell membrane and quantitative receptor expression. These larger SVs affect Fc receptors on both lymphoid and myeloid cell series, and nearly a third are uncharacterized in terms of genomic structure, resultant alterations in protein structure and impact on net biological function. Furthermore, persons of African- American heritage are over-represented in a number of these novel variant clusters. Current genotyping and whole genome sequencing efforts (eg, COVID-19 hg; COVIDhge) are unable to identify and define these SVs because of the segmental duplication of the FCGR locus with >98% homology of the paralogs. New, innovative technical approaches involving CRISPR/Cas9 targeted excision of the paralogs, coupled with long- read sequencing, now enable resolution of novel structural variations impacting biological function. Such knowledge will present the exceptional opportunity to enhance our understanding of disparities in COVID-19 disease, to anticipate the host response and potentially to adjust vaccination protocols. Accordingly, the goals of this supplement are to 1) immediately implement and apply our CRISPR/Cas9 digestion strategy and long- read sequence technology of Aim 1b to an expanded number of individuals originally proposed emphasizing ethnic minorities disproportionally affected by the COVID-19 pandemic, 2) expand the number of variant clusters to include all those found in African-American donors, 3) sequence the FCGR region in 100 patients with severe COVID-19 phenotype drawing on biospecimens drawn from across the Deep South, and 4) accelerate the analysis of sequencing data to identify the novel architectures and begin development of scalable genotyping strategies for detection of SVs and SNPs that are predicted to impact Fc receptor function/expression and influence the host response to acquired humoral immunity in both the acute and convalescent phases of disease. These goals will be enabled our COVID-19 Enterprise biobank and biospecimens from across the Deep South through our CTSA-driven CCTS Partner Network and will directly impact on our ability to identify individuals more or less likely to respond to effector antibody production.